Prior art inhibitors of 50.alpha.-reductase fail to provide an optimal combination of (1) lack of inherent androgenic activity and (2) ability to inhibit both of two different forms of testosterone 5.alpha.-reductase ("5.alpha.-reductase").
5.alpha.-reductase is an enzyme which catalyzes the conversion of the androgen, testosterone, to the much more potent androgen dihydrotestosterone ("DHT"). DHT is the more active androgen in many target organs (Anderson and Liao. Nature 219:277-279, 1968). The same enzyme catalyzes the conversion of androstenedione into androstanedione. Inhibitors of 5.alpha.-reductase inhibit biosynthesis of the products whose formation is catalyzed by 5.alpha.-reductase.
5.alpha.-reductase has been studied in different species (Liang et al. Endocrinology 117: 571-579, 1985). Its isolation and structure, and the expression of cDNA encoding it have been described (Andersson and Russell. Proc. Natl. Acad. Sci. 87:3640-3644, 1990).
Recent data have demonstrated the presence of at least two different genes expressing 5.alpha.-reductase in humans. Type I 5.alpha.-reductase (Andersson and Russell, Proc. Natl. Acad. Sci. 87, 3640-3644, 1990) is expressed at a low level in the human prostate while type II 5.alpha.-reductase is the predominant enzyme isoform expressed in this tissue (Andersson et al., Nature 354, 159-161, 1991).
The blockade of 5.alpha.-reductase has been intensively studied in view of developing pharmaceutical drugs for the therapy of diseases, such as prostate cancer. In European Patent Appln. No. EP 285 383 Ramusson et al. disclose the treatment of prostatic carcinoma with 17.beta.-N-monosubstituted-carbamoyl-4-aza-5.alpha.-androst-1-en-3-ones). Diseases for which 50.alpha.-reductase inhibitors are also being studied include acne, baldness (Rittmaster et al. J. Clin. Endocrinol. Metab. 65: 188-193, 1987) and benign prostatic hyperplasia (Metcalf et al., TiPS 10: 491-495, 1989).
The 4-aza-steroid N,N-diethyl-4-methyl-3-oxo-4-aza-5.alpha.-androstane-17.beta.-carboxamide, 4-MA has proven useful in inhibiting the formation of DHT from testosterone in rat prostate in vitro and in vivo (Brooks et al. Endocrinology 109: 830-836, 1981), thus reducing the testosterone-induced increase in ventral prostate weight in these animals. Another 4-aza-steroid, MK-906 (PROSCAR), has been found to cause a reduction in the intraprostatic concentration of DHT and a 25-30% reduction in prostatic size in men (Imperato-McGinley et al., Proc. 71st Ann. meet. Endocr. Soc., p. 332, abst 1639, 1989). However, Proscar is reported to be a potent inhibitor of the type II enzyme but a weak inhibitor of the type I enzyme (Andersson et al., Nature 354, 159-161, 1991). Such a low inhibitory potency on type I 5.alpha.-reductase probably explains why the highest doses of Proscar used in men generally fails to reduce serum dihydrotestosterone levels below 25 to 35% of control, thus leaving a highly significant concentration of circulating androgens (Vermeulen et al., The Prostate 14, 45-53, 1989). The inhibitory effect of the drug on prostatic volume in men remains limited at 25 to 35% over a period of 6 months (Stoner, J. Steroid Biochem. Mol. Biol. 37, 375-378, 1990). There is thus a need to develop compounds which can efficiently inhibit both type I and type II 5.alpha.-reductase and thus cause a more complete inhibition of circulating dihydrotestosterone levels. In U.S. Pat. No. 4,317,817, Belgian Patent Application No. 883 091 and British Patent Application. No. 204 8888, Blohm and Metcalf discuss the use of certain diazo-steroids as steroid 5.alpha.-reductase inhibitors. Metcalf et al describe the synthesis of related compounds in Tetrahedron Lett. 21, 15-18, 1980.
In EP Publication No. 343 954, EP Publication No. 375.347, U.S. Pat. No. 4,882,319, U.S. Pat. No. 4,937,237 and J. Med. Chem. 33: 937-942, 1990, Holt et al. discuss the use of certain A-ring aryl steroid derivatives as steroid 50.alpha.-reductase inhibitors.
In EP Publication No. 289 327 and Publication No. 427 434, on one hand, and in J. Steroid Biochem. 34: 571-575, 1989 and Biochemistry 29: 2815-2824, 1990, on the other hand, Holt and Levy discuss, respectively, the use of androstene- and pregnene-3-carboxylate derivatives as steroid-5.alpha.-reductase inhibitors.
In EP Publication No. 375 351, Holt et al. discuss the preparation of phosphoric acid substituted steroids as testosterone 5.alpha.-reductase inhibitors.
In EP Publication No. 271 219, EP Publication No. 314 199, and EP Publication No. 155 096, Rasmusson and Reynolds discuss the preparation of 17.beta.-substituted-4-aza-5.alpha.-androstenones as steroid-5.alpha.-reductase inhibitors.
Brooks, et al. (Steroid 47: 1-19, 1986; Prostate 9: 65-76, 1986) have reported 5.alpha.-reductase inhibiting and androgen-blocking activities for some 4-aza-steroids.
Rasmusson et al. discuss certain aza-steroids as inhibitors of rat prostatic 50.alpha.-reductase (in J. Med. Chem. 27: 1690-1701, 1984; idem 29: 2298-2315, 1986 and J. Biol. Chem. 259: 734-739, 1984).
In EP Publication No. 277 002, Holt et al. discuss 17.beta.-substituted-4-aza-5.alpha.-androstane-3-ones.
In EP Publication No. 271 220, Carlin et al. discuss the preparation of 17.beta.-(N-monosubstituted carbamoyl)-4-aza-5.alpha.-androstane-3-ones.
In EP Publication No. 200 859, Cainelli et al discuss the preparation of certain 4-aza-steroid derivatives which are stated to be steroidal 5.alpha.-reductase inhibitors.
In International Publication No. WO 91/12261, Panzeri et al. discuss the preparation of 17.beta.-substituted-4-aza-5.alpha.-androstan-3-one derivatives.
In U.S. Pat. No. 4,396,615, Steroids 38: 121-140, 1981 and J. Steroid Biochem. 19: 1491-1502, 1983; Petrow et al discuss certain 6-methylene progesterone derivatives stated to be inhibitors of steroid 5.alpha.-reductase.
In U.S. Pat. No. 4,377,584 (see e.g., column 13), U.S. Pat. No. 4,220,775 and in EP Publication No. 414 490 and 414 491, Rasmusson et al. discuss certain 17.beta.-substituted-4-aza-5.alpha.-androstanones (including acyl amino substitutions) as steroid-5.alpha.-reductase inhibitors.
In EP Publication No. 052799, Alig et al discuss the use of certain D-homosteroids as steroid 5.alpha.-reductase inhibitors.
In U.S. Pat. No. 4,191,759, Johnston and Arth discuss N-substituted-17.beta.-carbamoyl-androst-4-en-3-ones as steroid 5.alpha.-reductase inhibitors.
In BE 855 992, Benson and Blohm discuss steroidal inhibitors of testosterone 5.alpha.-reductase, for treating skin disorders.
In CA 970 692, Voight and Hsia discuss compounds inhibiting 5.alpha.-reductase activity.
In FR I 465 544, Jolly and Warnant discuss 4-aza-aromatic steroid derivatives as steroid 5.alpha.-reductase inhibitors.
In U.S. Pat. No. 4,087,461, Robinson discuss certain allenic steroids as testosterone 5.alpha.-reductase inhibitors.
In EP Publication No. 414 529, Metcalf discuss certain 17-substituted steroidal acids as testosterone 5.alpha.-reductase inhibitors (see e.g. the Abstract). See Also, Holt, et al., EP Publication No. 427,434.
In EP Publication No. 298 652, Bhattacharya disclose the synthesis of 4-aza-.DELTA.1-steroids.
In. U.S. Pat. No. 5,061,803 and 5,061,801, Williams discusses a method for the synthesis of 17.beta.-alkanoyl3-oxo-4-aza-5.alpha.-androst-1-enes and 3-oxo-4-aza-androst-1-ene 17.beta.-ketones.
In U.S. Pat. No. 5,061,802, Steinberg and Rasmusson discuss the preparation of 17.beta.-aminobenzoyl-4-aza-5.alpha.-androst-1-en-3-ones as benign prostatic hypertrophy agents.
Lan-Hargest et al. discuss the synthesis of bridged A ring steroids as 5.alpha.-reductase inhibitors (Tetrahedron Lett. 28:6117-6120, 1987).
Weintraub et al (in J. Med. Chem. 28: 831-833, 1985) discuss the preparation of 20-hydroxymethyl-4-methyl-4-aza-2-oxa-5.alpha.-pregnan-3-one as inhibitors of testosterone 5.alpha.-reductase.
Kadohama et al. (Cancer Res. 44: 4947-4954, 1984) discuss sodium 4-methyl-3-oxo-4-aza-5.alpha.-pregnane-20 (S) carboxylate inhibition of prostatic tumor 5.alpha.-reductase.
MacIndoe et al. in Steroid Biochem. 20, 1095-1100, 1984, discuss the 5.alpha.-reductase inhibiting effect, in MCF-7 human breast cancer cells and rat prostate, of certain 6-methylene steroids.
Liang et al (J. Biol. Chem. 256:7998-8005, 1981) discuss 17.beta.-N,N-diethylcarboxyamoyl-4-methyl-4-aza-5.alpha.-androstan-3-one as a reversible inhibitor of 5.alpha.-reductase.
Salomons and Doorenbos (J. Pharm. Sci. 63:19-23, 1974) and Doorenbos et al. (J. Pharm. Sci. 60:1234-1235, 1971; idem 62:638-640, 1973; Chem and Ind; 1322, 1970) discuss synthesis of 17.beta. amino 4-aza- steroids.
Nakayama et al. (J. Antibiotics XLII:1221-1229, 1989; idem, 1230-1234, 1989; idem, 1235-1240, 1989) discuss the isolation of WS-9659 from Streptomyces and its inhibitory activity on testosterone 5.alpha.-reductase.
In EP Publication No. 294 937 and Publication No. 294 035, Nakai et al. discuss the preparation, respectively, of cinnamoyl amide derivatives and ((benzoylamino)phenoxy) butanoic acid derivatives, as inhibitors of 5.alpha.-reductase.
U.S. Pat. 5,026,882 and EP Publication No. 375 349 relates to certain steroid-3-phosphinic acid compounds for use as inhibitors of steroid 5.alpha.-reductase. These patents also summarize in their description of the related art, numerous compounds which are stated to be prior art 5.alpha.-reductase inhibitors. See, for example, Table I of U.S. Pat. No. 5,026,882 and the discussion in the prior art section of the patent.
EP Publication No. 435 321 relates to A-nor-steroid-3-carboxylic acid derivatives, which reportedly exhibit 5.alpha.-reductase inhibition.
In International Publication No. WO 91/13060 and EP Publication No. 458 207, Okada et al. discuss the preparation of Indole derivatives as testosterone 5.alpha.-reductase inhibitors.
Salle, et al., "17.beta.-acylurea Derivatives of 4-Azasteroids as Inhibitors of Testosterone 5.alpha.-Reductase" relates to studies regarding the effectiveness on 5.alpha.-reductase of a new series of 17.beta.-acylurea substituted derivatives.
U.S. Pat. No. 5,053,403 describes the use of certain androgen receptor blocking agents together with certain 5.alpha.-reductase enzyme inhibitor in the treatment or prevention of sebaceous gland hypertrophy, hirsutism and male-pattern baldness.
Prior art inhibitors of 5.alpha.-reductase are not believed to fully inhibit both forms of 5.alpha.-reductase without exhibiting or causing undesirable androgenic or other hormonal activity.